The activity of nucleoside transport systems can modulate the toxicity of both nucleoside and non-nucleoside antimetabolites. This research is directed at further increasing the therapeutic ratio of methotrexate and cytosine arabinoside through the use of nucleoside transport inhibitors. Such inhibitors have been shown in vitro to increase the toxicity of methotrexate by limiting the availability of thymidine, and to decrease the toxicity of cytosine arabinoside by decreasing transport of this drug. Ongoing studies are directed at determining whether nucleoside transport inhibitors can modulate the toxicity of these antimetabolites in vivo, and whether this results in an improved therapeutic outcome in the L1210 murine leukemia system. High pressure liquid chromatographic techniques have been developed for the quantitation of nucleoside transport inhibitors in serum, and this technique will be applied to measure the basic pharmacologic parameters of these agents.